T cell trafficking is a fundamental component of adaptive immunity, both in terms of effectively clearing foreign pathogens as well as limiting autoimmunity. Naive T cell migration is limited to a series of peripheral secondary lymphoid organs interconnected via blood and lymphatic vessels whereas activated effector T cells can escape this circulatory loop and enter peripheral tissues. To achieve these distinct migration patterns, naive and effector T cells respond to diverse chemokine gradients via homeostatic and inflammatory chemokine receptors (CRs), respectively. T cells acquire inflammatory CRs during an immune response when naive T cells interact with activated antigen presenting cells, however, the T cell-intrinsic molecular mechanisms involved in this receptor regulation are currently unknown. In this regard, preliminary evidence indicates that the transcription factor, Kr[unreadable]ppel-like factor 2 (Klf2), may play a crucial role in controlling CR gene expression. Naive T cells lacking Klf2 express inflammatory CRs and acquire novel trafficking patterns, including naive T cell distribution in peripheral non-secondary lymphoid organs. In addition, a subset of naive T cells appear to downregulate homeostatic CRs. Therefore, we hypothesize that Klf2 regulates transcription of CR genes, which is necessary for maintaining naive T cells in a homeostatic circulatory pattern and restricting T cell-mediated immune responses. This central hypothesis will be addressed by achieving three independent goals: (Aim 1) identifying Klf2-dependent mechanisms that repress inflammatory CRs and induce homeostatic CR gene transcription;(Aim 2) assessing the functional status of these CRs using Klf2-deficient T cells and determining which CRs are responsible for aberrant naive Klf2-deficient T cell trafficking in vivo, and;(Aim 3) establishing how unrestrained naive T cell trafficking affects cellular immunity at the cell-intrinsic level (anergy versus intact T cell effector functions) as well as at a host level (immunocompromised host versus effective pathogen clearance versus autoimmunity). These studies should provide important information concerning CR gene regulation in naive T cells, the affect atypical CR expression has on T cell migration and the immunological consequences of naive T cell trafficking into peripheral tissues. This research has important implications both with regards to broad biological processes such as CR regulation as well as clinical conditions such as pathogen clearance and T cell-mediated diseases like autoimmune myocarditis. Public Health Relevance: T lymphocytes mediate immune responses, both desired (such as clearance of disease-causing viruses) and undesired (such as attacking self-tissues in autoimmune diseases). The goal of this project is to determine how T cells migrate to various tissues to carry out these diverse functions and find out what happens when this migration process malfunctions. This research has important implications both with regards to pathogen clearance and autoimmunity, with potential therapeutic applications.